Pharmacokinetic Study of the HCV Protease Inhibitor Boceprevir and the HIV Integrase Inhibitor Raltegravir (OPAL)

The objective of this study is to evaluate the effect of boceprevir (steady state) on the pharmacokinetics of a single dose of raltegravir. The effect on the boceprevir pharmacokinetics of a single dose raltegravir will also be evaluated (compared to historical controls). Furthermore, the safety profile of the combination is studied.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HCV Infections
• Intervention / Treatment: Drug: boceprevir; Drug: raltegravir

Detailed Description

A considerable percentage of HIV infected patients is also infected with the hepatitis C virus (HCV). HIV/HCV co-infected patients are likely to simultaneously use treatment for their HIV infection as well as HCV treatment. Therefore, it is important to know if drug-drug interactions occur when combining those treatments.

Raltegravir is an HIV integrase inhibitor and approved by the FDA in 2007. Boceprevir is a potent HCV NS3 serine protease inhibitor and is currently in Phase III clinical development.

Combined use of boceprevir and raltegravir is not expected to give a major drug-drug interaction as raltegravir is not a CYP3A substrate and thus will not be affected by the strong inhibition of CYP3A by boceprevir. Raltegravir is metabolized by UGT but boceprevir is not known to influence UGT. However, recent data indicate that raltegravir is a P-gp substrate and boceprevir is a substrate and a moderate inhibitor of P-gp in vitro.

Even when no drug interaction is expected, it may be recommended to collect sufficient evidence that this is the case as in many cases un-expected drug-drug interactions have been observed in the past.

The current study is designed to evaluate the effect of steady state boceprevir on the pharmacokinetics of a single dose of raltegravir and the safety profile when used in combination. Furthermore the effect of a single dose raltegravir is studied on the pharmacokinetics of steady state boceprevir in comparison with historical controls.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • CRCN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject is at least 18 and not older than 55 years at scree-ning.
• Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to the first dosing
• Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
• Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
• Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, haematology and urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges. If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
• Subject has a normal blood pressure and pulse rate, according to the Investigator's judgement.

Exclusion Criteria:

• Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
• Positive HIV test.
• Positive hepatitis B or C test.
• Pregnant female (as confirmed by an HCG test performed less than 4 weeks before Day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the trial.
• Therapy with any drug (for two weeks preceding dosing), ex-cept for paracetamol.
• Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal and hepatic disorders, hormonal disorders (especially diabetes mellitus), coagulation disorders.
• Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
• History of or current abuse of drugs, alcohol or solvents.
• Inability to understand the nature and extent of the trial and the procedures required.
• Participation in a drug trial within 60 days prior to the first dose.
• Donation of blood within 60 days prior to the first dose.
• Febrile illness within 3 days before the first dose.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: boceprevir + raltegravir; 9 days of boceprevir 800mg TID; day 10 two doses of boceprevir 800mg and one dose of raltegravir 400mg	Drug: boceprevir; 10 days of boceprevir 800mg TID; Drug: raltegravir; raltegravir 400mg single dose; Other Names: Isentress
Active Comparator: raltegravir alone; single dose of raltegravir 400mg	Drug: raltegravir; raltegravir 400mg single dose; Other Names: Isentress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
raltegravir concentrations	To determine the effect of chronic use of boceprevir on the single-dose pharmacokinetics of raltegravir 400mg in healthy volunteers	during 12hours on two occasions

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
adverse events	to determine the safety of a single dose of raltegravir 400mg when combined with chronic use of boceprevir	entire study
boceprevir concentrations	To determine the effect of a single-dose pharmacokinetics of raltegravir 400mg on chronic use of boceprevir in healthy volunteers	during 8 hours on one occasion; predose 4 times over a period of 10 days

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• de Kanter CT, Blonk MI, Colbers AP, Schouwenberg BJ, Burger DM. Lack of a clinically significant drug-drug interaction in healthy volunteers between the hepatitis C virus protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir. Clin Infect Dis. 2013 Jan;56(2):300-6. doi: 10.1093/cid/cis824. Epub 2012 Sep 21.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: January 26, 2011
• First Submitted That Met QC Criteria: February 1, 2011
• First Posted (Estimate): February 2, 2011

Study Record Updates

• Last Update Posted (Actual): December 1, 2020
• Last Update Submitted That Met QC Criteria: November 26, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: HIV infections; pharmacokinetics; raltegravir; boceprevir; interaction; HCV infections
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; HIV Infections; Infections; Communicable Diseases; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Raltegravir Potassium
• Other Study ID Numbers: UMCN-AKF 10.05